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The expression of the follicle-stimulating hormone receptor in spermatogenesis.

ABSTRACT: Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capacity of the testis. The regulation of the expression of the FSH receptor (FSHR) gene is very cell specific and plays an initial role in the ultimate response of the Sertoli cells to FSH. The extreme cell specificity and the importance of the FSH response to spermatogenesis have led to an extensive characterization of the promoter of the FSHR gene. Several widely expressed transcription factors - including USF 1 and 2, GATA-1, and SF-1 and potential elements such as an E2F site and an Inr region - have been shown to contribute to the maximal transcription of the transfected FSHR gene. However, these experiments have failed to provide clues as to the cell-specific expression of the FSHR gene. In both cell transfections and in transgenic mice, the promoter can direct expression of transgenes promiscuously. The rodent FSHR promoter contains conserved CpG dinucleotides that were shown to be methylated in nonexpressing cells and tissue but unmethylated in Sertoli cells. The methylated CpG sites could interfere with the binding of general transcription factors and/or lead to a repressive chromatin structure in the nonexpressing cells. While yet-undiscovered cell-specific factors may play a role in the expression of the FSHR gene, repression and activation of local chromatin structure are likely to be involved.

SUBMITTER: Heckert LL

PROVIDER: S-EPMC1496959 | biostudies-literature | 2002

REPOSITORIES: biostudies-literature

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The expression of the follicle-stimulating hormone receptor in spermatogenesis.

Heckert Leslie L LL Griswold Michael D MD

Recent progress in hormone research 20020101

Results from experiments using mouse models suggest that the role of follicle-stimulating hormone (FSH) in spermatogenesis is the regulation of Sertoli cell proliferation and, ultimately, the size and spermatogenic capacity of the testis. The regulation of the expression of the FSH receptor (FSHR) gene is very cell specific and plays an initial role in the ultimate response of the Sertoli cells to FSH. The extreme cell specificity and the importance of the FSH response to spermatogenesis have le ...[more]

PMID: 12017540

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Project description:BackgroundSeveral alternatively-spliced mRNA transcripts of the follicle stimulating hormone receptor (FSHR) have been identified in sheep, including FSHR-1 (G protein-coupled form), FSHR-2 (dominant negative form), and FSHR-3 (growth factor type-1 form). Our objective was to determine which of these variants is predominantly expressed in follicles collected from ewes at various times after estrus.MethodsSuffolk-cross ewes (n = 8) were allowed to come into estrus naturally and were euthanized 24 (n = 3), 36 (n = 3), or 48 (n = 2) hours after the onset of estrus. All visible follicles were measured, aspirated and pooled according to follicular diameter: small (<= 2.0 mm), medium (2.1-4.0 mm), large (4.1-6.0 mm), and preovulatory (> = 6.1 mm). Aspirated cells were separated from follicular fluid by centrifugation. Total RNA was extracted from cell pellets and reverse transcribed. The resulting cDNA was subjected to qPCR, using primer sets designed to amplify each variant specifically. Gene expression was normalized to that of beta-actin within samples, and compared by analysis of variance with the level of significant differences set at p < .05.ResultsRelative expression of FSHR-3 exceeded that of both FSHR-1 and FSHR-2 in medium follicles, and tended to be higher in small follicles (p = .09) regardless of time after onset of estrus, and thus results from different time points were pooled. Expression of FSHR-3 was greater than that of FSHR-2 and luteinizing hormone receptor (LHR) in small and medium follicles. Expression of LHR was greatest in preovulatory follicles.ConclusionsThese experiments show that in addition to the well characterized G protein-coupled form of the FSHR, alternatively spliced variants of the FSHR may participate in follicular dynamics during follicular waves of the sheep estrous cycle. Furthermore, these results indicate that an "alternatively" spliced form of the FSHR (FSHR-3) is the predominant form of the FSHR in the sheep.

Project description:Previous work showed that pharmacological inactivation of Igf-binding proteins (Igfbps), modulators of Igf activity, resulted in an excessive differentiation of type A undifferentiated (Aund) spermatogonia in zebrafish testis in tissue culture when Fsh was present in the incubation medium. Using this testis tissue culture system, we studied here the regulation of igfbp transcript levels by Fsh and two of its downstream effectors, Igf3 and 11-ketotestosterone (11-KT). We also explored how Fsh-modulated igfbp expression affected spermatogonial proliferation by adding or removing the Igfbp inhibitor NBI-31772 at different times. Fsh (100?ng/mL) decreased the transcript levels of igfbp1a, -3, and -6a after 1 or 3?days, while increasing igfbp2a and -5b expression, but only after 5?days of incubation. Igf3 down-regulated the same igfbp transcripts as Fsh but with a delay of at least 4?days. 11-KT increased the transcripts (igfbp2a and 5b) that were elevated by Fsh and decreased those of igfbp6a, as did Fsh, while 11-KT did not change igfbp1a or -3 transcript levels. To evaluate Igfbps effects on spermatogenesis, we quantified under different conditions the mitotic indices and relative section areas occupied by the different spermatogonial generations (type Aund, type A differentiating (Adiff), or type B (B) spermatogonia). Igf3 (100?ng/mL) increased the area occupied by Adiff and B while decreasing the one for Aund. Interestingly, a concentration of Igf3 that was inactive by itself (25?ng/mL) became active in the presence of the Igfbp inhibitor NBI-31772 and mimicked the effect of 100?ng/mL Igf3 on spermatogonia. Studies exploiting the different dynamics of igfbp expression in response to Fsh and adding or removing NBI-31772 at different times showed that the quick downregulation of three igfbp as well as the delayed upregulated of two igfbps all support Igf3 bioactivity, namely the stimulation of spermatogonial differentiation. We conclude that Fsh modulates, directly or via androgens and Igf3, igfbp gene expression, supporting Igf3 bioactivity either by decreasing igfbp1a, -3, -6a or by increasing igfbp2a and -5b gene expression.

Project description:BackgroundDesensitization of FSH response by down-regulation of FSHR transcription is critical for FSH action.ResultsChromatin modifier MTA2 participates in the down-regulation of FSHR transcription.ConclusionThe FSH/Ar/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate FSH transduction events in Sertoli cells.SignificanceOur findings provide new insights into mechanisms by which FSH is deregulated in male infertile patients. The effect of follicle-stimulating hormone (FSH) on spermatogenesis is modulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells (SCs). One underlying mechanism is the down-regulation of the expression levels of the FSH receptor (FSHR) gene after exposure to FSH. Here we report that metastasis-associated protein 2 (MTA2), a component of histone deacetylase and nucleosome-remodeling complexes, as a gene product induced directly by testosterone or indirectly by FSH, is exclusively expressed in SCs. Stimulation of SCs with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional androgen receptor. Furthermore, MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. Abolishment of endogenous MTA2 by siRNA treatment disrupted the desensitization of the FSH response and thereafter impaired the FSH-dependent secretory function of SCs. From a clinical standpoint, deregulated expression of MTA2 in SCs of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that the FSH/androgen receptor/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate the transduction events of SCs in response to FSH. These data also underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs.

Dataset Information

The expression of the follicle-stimulating hormone receptor in spermatogenesis.

Publications

The expression of the follicle-stimulating hormone receptor in spermatogenesis.

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